The use of visible and near infrared (NIR) light in clinical practice is rapidly growing (Fanini S et al, Appl. Opt. 1998, 37, 1982-1989).
Compounds absorbing or emitting in the visible, or NIR, or long wave region of the electromagnetic spectrum are potentially useful for optical tomographic imaging, or endoscopic visualization.
Common methods for cancer diagnosis rely on the physical detection of a palpable tumor mass or the use of different forms of roentgenography, scintigraphy, ultrasound and imaging techniques for tissue imaging which require the presence of a significant tumor mass (Shaw M L et al, Invest. Radiol. 1993, 28, 138-139).
Large molecules such as antibodies have, for scintigraphic imaging, the disadvantage that they are preferably taken up by the liver and can elicit adverse immunogenic reactions in humans (Guyton, A C, textbook of medical physiology. Philadelphia, Pa., W.B. Saunders CO 1996). Recent studies have demonstrated that attachment of chelating agents to small-molecular peptides can be used to target tumors without loss of receptor affinity (Kweckenboom D J et al, Eur. J. Nucl. Med. 1998, 25, 1284-1292).
Such advantages include enhanced localization in tumors, and rapid clearance from the blood.
Recently, it has been shown that the CXCR4-receptor is not only involved in the entry of HIV (N. Levy, Engl. J. Med., 335, 29, 1528-1530) but also in the chemotactic activity of cancer cells, such as breast cancer metastasis or metastasis of ovarian cancer (A. Muller, B. Homey, H. Soto, N. Ge, D. Catron, M. E. Buchanan, T. Mc Clanahan, E. Murphey, W. Yuan, S. N. Wagner, J. Luis Barrera, A. Mohar, E. Verastegui, A. Zlotnik, Nature 2001, 50, 410, J. M. Hall, K. S. Korach, Molecular Endocrinology, 2003, 1-47); non-Hodgin's Lymphoma (F. Bertolini, C. DellÀgnola, P. Manusco, C. Rabascio, A. Burlini, S. Monestiroli, A. Gobbi, G. Pruneri, G. Martinelli, Cancer Research 2002, 62, 3106-3112); lung cancer (T. Kijima, G. Maulik, P. C. Ma, E. V. Tibaldi, R:E. Turner, B. Rollins, M. Sattler, B. E. Johnson, R. Salgia, Cancer Research 2002, 62, 6304-6311); melanoma; prostate cancer; kidney cancer; neuroblastomia; pancreatic cancer; multiple myeloma; or chronic lymphocytic leukemia (H. Tamamura et al. Febs Letters 2003, 550 79-83). Blocking the chemotactic activity with a CXCR4 inhibitor should stop the migration of cancer cells.
The CXCR4 receptor has also been implicated in the growth and proliferation of tumors. It was shown that activation of the CXCR4 receptor was critical for the growth of both malignant neuronal and glial tumors, and small-cell lung tumors. Moreover, systemic administration of the CXCR4 antagonist AMD3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells (Rubin J B, Kung A L, Klein R S, Chan J A, Sun Y, Schmidt K, Kieran M W, Luster A D, Segal R A. Proc Natl Acad Sci USA. 2003 100(23):13513-13518; Barbero S, Bonavia R, Bajetto A, Porcile C, Pirani P, Ravetti J L, Zona G L, Spaziante R, Florio T, Schettini G. Stromal Cancer Res. 2003, 63(8):1969-1974; Kijima T, Maulik G, Ma P C, Tibaldi E V, Turner R E, Rollins B, Sattler M, Johnson B E, Salgia R. Cancer Res. 2002; 62(21):6304-6311, and Cancer Res. 2002; 62(11):3106-3112. High level of expression of chemokine receptors has been associated with tumor dissemination and poor prognosis for colorectal cancer (Schimanski C. C. et al, Clinical Cancer Research 2005 11, 1743-1750); prostate cancer (Arya M. et al, J. Experimental. Therapeutics and Oncology 2004, 4, 291-303); and malignant melanoma (Scala S. et al, Clinical Cancer Research 2005, 11, 1835-1841).
There is increasing evidence suggesting that chemokines in general, and the interaction between the chemoattractant CXCL12/stromal cell-derived factor-1alpha and its receptor CXCR4 in particular, play a pivotal role in angiogenesis. Chemokines induce angiogenesis directly by binding their cognate receptors on endothelial cells, or indirectly by promoting inflammatory cell infiltrates, which deliver other angiogenic stimuli. A number of pro-inflammatory chemokines including interleukin 8 (IL-8), growth-regulated oncogene, stromal cell-derived factor 1 (SDF-1), monocyte chemotactic protein 1 (MCP-1), eotaxin 1, and I-309 have been shown to act as direct inducers of angiogenesis (Chen X, Beutler J A, McCloud T G, Loehfehn A, Yang L, Dong H F, Chertov O Y, Salcedo R, Oppenheim J J, Howard O M. Clin Cancer Res. 2003 9(8):3115-3123; Salcedo R, Oppenheim J J. Microcirculation 2003 (3-4):359-370).
Therefore, receptor specific tumor localization of dye-conjugated CXCR4-inhibitors is highly desirable and could in addition be used as inhibitors for treatment of cancer.